title: Identification of MET genomic amplification, protein expression and alternative splice isoforms in neuroblastomas.
abstract: BACKGROUND
  Crizotinib, a dual anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition (MET) tyrosine kinase inhibitor, is currently being evaluated for the treatment of neuroblastoma. Its effects are thought to be mediated mainly via its activity against ALK. Although MET genomic/protein expression status might conceivably affect crizotinib efficacy, this issue has hitherto not received attention in neuroblastomas.
  
  
  OBJECTIVE
  MET genomic and protein expression status was characterised by silver in situ hybridisation and immunohistochemistry (IHC) respectively, in a cohort of 54 neuroblastoma samples. MET splice isoforms were characterised in 15 of these samples by quantitative PCR.
  
  
  RESULTS
  One case (1/54; prevalence 1.85%) displayed MET genomic amplification, while another case (1/54; prevalence 1.85%) displayed strong membranous MET protein expression (IHC score 3+). Alternative exon 10-deleted and exon 14-deleted MET splice isoforms were identified.
  
  
  CONCLUSIONS
  MET amplification and protein expression, although low in prevalence, are present in neuroblastomas. This has implications when crizotinib is employed as a therapeutic agent in neuroblastomas. Additionally, the existence of alternatively spliced MET isoforms may have clinical and biological implications in neuroblastomas.
authors.affiliation: Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore.
authors.forename: Benedict
authors.initials: B
authors.lastname: Yan
authors.forename: Malcolm
authors.initials: M
authors.lastname: Lim
authors.forename: Lihan
authors.initials: L
authors.lastname: Zhou
authors.forename: Chik Hong
authors.initials: CH
authors.lastname: Kuick
authors.forename: May Ying
authors.initials: MY
authors.lastname: Leong
authors.forename: Kol Jia
authors.initials: KJ
authors.lastname: Yong
authors.forename: Lele
authors.initials: L
authors.lastname: Aung
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.forename: Kenneth T E
authors.initials: KT
authors.lastname: Chang
mesh_terms: D017398:Alternative Splicing; D000077548:Anaplastic Lymphoma Kinase; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D000077547:Crizotinib; D058750:Epithelial-Mesenchymal Transition; D005091:Exons / Q000235:genetics; D005260:Female; D023281:Genomics; D006801:Humans; D017403:In Situ Hybridization; D007223:Infant; D007527:Isoenzymes; D008297:Male; D009154:Mutation; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D046888:Tissue Array Analysis; D016896:Treatment Outcome
chemical_list: D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases
keywords: Molecular Pathology; Neuroblastoma; Oncogenes; Oncology; Paediatric Pathology